The Induction of Antigen 85B-Specific CD8+ T Cells by Recombinant BCG Protects against Mycobacterial Infection in Mice

Abstract

Mycobacterium tuberculosis (Mtb) infection remains a major health problem worldwide. Although the Bacillus Calmette-Guérin (BCG) vaccine is the most widely used vaccination for preventing tuberculosis (TB), its efficacy is limited. We previously developed a new recombinant BCG (rBCG)-based vaccine encoding the Ag85B protein of M. kansasii (Mkan85B), termed rBCG-Mkan85B, and its administration is followed by boosting with plasmid DNA expressing the Ag85B gene (DNA-Mkan85B). Previously, we identified MHC-I (H2-Kd)-restricted epitopes that highly cross-react with those of Mtb in BALB/c (H2d) and CB6F1 (H2b/d) mice. We also reported that the rBCG-Mkan85B/DNA-Mkan85B prime–boost vaccination protocol protected CB6F1 mice against M. kansasii infection. In this study, to investigate the protective effect of our novel rBCG against Mtb infection, CB6F1 mice were either left unimmunized or immunized with the BCG, rBCG-Mkan85B, or rBCG-Mkan85B/DNA-Mkan85B vaccine for 10 weeks prior to inhalation exposure to the virulent Mtb Erdman strain for another 6 weeks. Compared with the BCG and rBCG-Mkan85B vaccinations, the rBCG-Mkan85B/DNA-Mkan85B prime–boost vaccination protocol significantly reduced the numbers of pulmonary colony-forming units (CFUs). Moreover, the rBCG-Mkan85B/DNA-Mkan85B prime–boost vaccination induced antigen-specific polyfunctional CD4+ and CD8+ T cells. These results suggest that CD8+ T-cell immunity to immunodominant epitopes of Mtb is enhanced by rBCG vector-based immunization. Thus, rBCG vector-based vaccinations may overcome the limited ability of the current BCG vaccine to elicit TB immunity.

Recombinant BCG vaccine expressing multistage antigens of Mycobacterium tuberculosis provides long-term immunity against tuberculosis in BALB/c mice

“…The pie charts of cytokine production profiles for CD4 + T cells also reflected that rBCG-ECD003 could induce magnitude higher proportions of CD4 + T cells expressing IL-2 alone or IFN-γ + IL-2 + . In contrast, the cytokine production profiles induced by BCG were mainly dominated by IFN-γ + CD4 + T cells, which aligns with the findings of Komine-Aizawa S et al 30 Additionally, IFN-γ + CD4 + T cells are considered to have an effector phenotype, while IL-2-expressing T cells tend to exhibit a central memory phenotype in BCG-vaccinated infants. 31 However, the higher differentiation of effector phenotype CD4 + T leads to a reduced capacity to enter the infected site.…”

“… 32 Apart from CD4 + T cells, recent studies have highlighted the contribution of CD8 + T cells to the protective immunity against TB. 30 , 33 , 34 Unfortunately, we did not observe a preference for the induction of polyfunctional CD8 + T cells in the rBCG-ECD003 group which may be attributed to inferior activation of cross-priming capacity by mycobacteria.…”